Redefining the metabolic landscape through TGF-beta/Activin signaling in Drosophila melanogaster

Multicellular organisms assess their nutritional state and adapt their metabolic landscape to match their energy demands. In this thesis, we address a longstanding conundrum of how an organism coordinates digestive enzyme expression in response to its nutritional status. Hydrolysis of food materials by endogenous or microbial-derived digestive enzymes precedes absorption through the gut lumen. Thus, modulation of endogenous digestive mechanism represents a pragmatic step to limit the uptake of nutrients when nutrients are in abundance. In Drosophila melanogaster, it is known that dietary glucose represses amylase transcript and enzymatic activity, in a process known as glucose repression. Here, we show that glucose reduces the expression of many carbohydrases, lipases, and glucose transporters, presumably to prevent nutritional overload after feeding. We found that the repression of carbohydrases is effected by nutritious sugars through the induction of the TGF-beta ligand, Dawdle. Interestingly, glucose repression of digestive enzymes is dependent upon the induction of Dawdle in the fat body, a tissue functionally analogous to the mammalian liver and adipose tissue. Dawdle is then transported via the circulation to activate TGFβ/Activin signaling in the midgut, leading to the repression of digestive enzymes expression. We later discovered that Dawdle expression in the fat body is regulated by the evolutionarily conserved Mio-bigmax transcription factor complex. In addition, expression of Dawdle must be tightly coordinated to reflect the nutritional state of adult flies, as flies overexpressing Dawdle are sensitive to starvation and have their TAG and glycogen stores rapidly depleted upon nutrient limitation. Thus, our results are consistent with a model whereby fat body derived Daw functions as a nutritional cue for carbohydrates to modulate metabolic responses in distal tissues. Its induction provides the nutritional signal to repress carbohydrate digestive capacity and stimulate peripheral insulin signaling. In conclusion, our study identifies the TGFβ/Activin signaling as a critical mechanism for carbohydrate homeostasis. Our results indicate that the fat body functions as a carbohydrate sensing tissue, which through the secretion of the TGFβ ligand, Daw, regulates organism-wide carbohydrate metabolism. Our work in Drosophila is likely to have a broader scientific impact by placing a pathway known for its role in development, immunity, and cancer, as an integral component for sugar sensing and metabolism.